The purpose of this grant is to investigate the efferent innervation of the peripheral vestibular apparatus. Knowledge of the neurotransmitters and projections from brainstem efferent neurons to the peripheral labyrinth will help us to understand the role of this system in health and disease. We build on our past work suggesting that vestibular efferent neurons are heterogeneous in their transmitter composition and peripheral targets. Such heterogeneity challenges our long-held view that vestibular efferents are a nonspecific system. Experiments are done in the chinchilla and will concentrate on the peripheral organization of the efferent system. Anatomical, as well as immunohistochemical and other molecular approaches, are used to study the structural organization of the efferent system with both confocal and electron microscopy. Efferent neurons in the periphery are identified by means of anterograde tracer injections into their brainstem nuclei of origin and their distinctive synaptic profiles in the periphery. Afferent classes are identified by means of specific immunohistochemical markers (calretinin, peripherin). Efferent structure is correlated with hair cell and afferent classes and with the regional organization of the cristae and maculae. Specific aims are: 1) to determine by anterograde tracing the projection patterns and terminal fields of ipsilaterally-, contralaterally-, and bilaterally-projecting efferent neurons in the cristae and maculae: 2) to specify nicotinic. muscarinic and CGRP receptor subtypes on hair cells and afferents: and 3) to examine subcellular mechanisms of efferent action, specifically the localization of calcium-related pumps and channels in subsynaptic cisterns. The intent is to produce a body of morphological, neurochemical and cell biological knowledge from which physiologically and pharmacologically testable hypotheses can be derived. [unreadable] [unreadable] [unreadable]